Afferent neural activity arising from peripheral baroreceptors monitoring cardiovascular function not only produces CNS-mediated reflex adjustments of the circulation, but also activates CNS systems that inhibit pain. The primary goals of this proposal are to identify medullary and spinal cord structures of this cardiovascular pain regulatory network in the rat, establish the efficacy of putative transmitters of primary baroreceptor afferents in producing hypoalgesia or a diminished sensitivity to pain, and determine the range of influence of this network. The regions of the medulla and spinal cord under investigation include the nucleus tractus solitarius (NTS), nucleus raphe magnus (NRM), lateral reticular nucleus (LRN), dorsolateral funiculus (DLF), and ventrolateral funiculus (VLF) based upon their established roles in both cardiovascular and nociceptive function. The importance of these regions in the production of hypoalgesia will be determined through the use of electrolytic and mechanical lesions, and pressure microinjection of pharmacologic agonists and antagonists. Hypoalgesia will be induced by several peripheral cardiovascular stimulus operations including physiological (volume expansion), pharmacological (administration of veratrum alkaloids, enkephalinamide, phenylephrine, or norepinephrine), or electrical activation of cardiopulmonary or sinoaortic baroreceptor afferents. Pain sensitivity will be indexed through behavioral responses in tail-flick, hot-plate, and flinch-jump tests. These experiments will serve to delineate the nature of cardiovascular-pain regulatory interactions and thereby establish how physiological stimuli activate endogenous systems that inhibit pain. These studies will also clarify the mechanisms which mediate a diverse range of phenomena including stress-induced analgesia, the action of peripherally circulating enkephalins in producing analgesia, and the inhibition of cardiac pain.